The present invention relates to a novel process for preparing [S]-2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran (hereinafter referred to as "[S]-befunolol") or salts thereof, more particularly to a process for preparing the [S]-befunolol or salts thereof through optically active [S]-(+)-2-acetyl-7-(2,3-epoxypropoxy)benzofuran (hereinafter referred to as "SEBF").
SEBF is important as an intermediate for synthesis of various optically active organic compounds, particularly as an intermediate for synthesis of [S]-(-)-befunolol hydrochloride and the other salts thereof which are very useful as a .beta.-adrenergic blocking agent (hereinafter referred to as ".beta.-blocker") in prevention and treatment of heart disease such as arrhythmia or angina pectoris and hypertension and treatment of glaucoma as disclosed in Japanese Examined Patent Publication No. 20,063/1975.
Most .beta.-blockers have a peculiar moiety represented by the following formula: ##STR1## and accordingly optical isomers based on the symmetric carbon atom (carbon atom with star mark) are present. In many .beta.-blockers hitherto known, it is known that an optically active compound having [S]-configuration (hereinafter referred to as "S-form") has in general a higher pharmacological activity than its mirror-image isomer (hereinafter referred to as "R-form") and the racemic compounds as, for instance, reported in J. Med. Chem., 11, 1118(1968). Befunolol hydrochloride is not an exception thereto, and for instance, it is admitted that in a test examining antagonism against heart contraction enhancement of isoproterenol in dogs, the S-form has about 40 times higher activity than the R-form. Therefore, it has been demanded to develop a process for preparing [S]-befunolol selectively and easily in high yields. In such a process, SEBF is one of the useful and practical intermediates.
As representative processes for obtaining [S]-.beta.-blockers, there are well known (1) an optical resolution process and (2) a process in which naturally abundant [D]-mannitol is used as a chiral source and the asymmetric carbon atom thereof is introduced into a desired compound. The optical resolution process (1) has the drawback that a resolving reagent is difficult to obtain. Therefore, in case of intending industrial preparation, the process (2) utilizing [D]-mannitol is rather superior and many studies thereof have been made. The present inventors have also made a study in line with the same object on a process capable of synthesizing SEBF into which the asymmetric carbon atom of [D]-mannitol is introduced by a novel method.
The prior art in the field of this invention teaches the reaction of various optically active reacting reagents obtained from [D]-mannitol, e.g. [R]- or [S]-epichlorohydrin (cf. Japanese Examined Patent Publication No. 43775/1971), [R]- or [S]-mesyloxymethyloxirane [cf. J. Am. Chem. Soc., 101, 3666(1979)], and [R]- or [S]-3-tosyloxy-1,2-propanediolacetonide (cf. Japanese Unexamined Patent Publication No. 77331/1975), with a phenolic compound under a basic condition. That is, these prior art teachings all utilize nucleophilic substitution of phenoxide anion (ArO.sup.-) produced during the reaction for the leaving group (halogen atom, mesyloxy group, p-toluenesulfonyloxy group) in the reacting reagents. However, if such a nucleophilic substitution reaction is applied to the preparation of SEBF, the desired substitution product is hard to obtain in high yields owing to the considerably basic condition utilized.
In the preparation of 2-acetyl-7-(2,3-epoxypropoxy)benzofuran racemic compounds, there has been adopted a process in which 2-acetyl-7-hydroxybenzofuran of the formula: ##STR2## is reacted with a large excess of (.+-.)-epichlorohydrin by employing piperidine hydrochloride which is a weak basic compound, as a base catalyst, as known from Japanese Examined Patent Publication No. 20063/1975. However, application of this process to the preparation of SEBF requires a large quantity of an expensive optically active compound, e.g. optically active epichlorohydrin, and accordingly has little practical value. Therefore, in the preparation of SEBF, it is ideal to utilize an entirely different process to replace conventional processes utilizing the nucleophilic substitution reaction. For instance, a process could be used in which the reaction is able to proceed under such a moderate condition that the reaction system is maintained in the vicinity of neutral condition throughout the reaction.
It is an object of the present invention to provide a process for preparing optically active [S]-befunolol and pharmaceutically acceptable salts thereof in high yields.
Another object of the invention is to provide a process for preparing an optically active [S]-2-acetyl-7-(2,3-epoxypropoxy)benzofuran (SEBF) which can be easily converted into [S]-befunolol.
These and other objects of the present invention will become apparent from the description hereinafter.